Fertility Flashcards
Oogenesis
Primordial germ cells invade genital ridge then become eggs/sperm, first identifiable at 3 weeks, undergoes many cycles of mitosis
Genital ridge becomes gonad, gonadal differentiation linked to PGC development
Oocyte Differentiation
Germ cells enter the ovary to become oogonia-egg precursors that divide by mitosis
Oogonia mitosis stops and enter meiosis to produce primary oocytes which are diploid
Mitotic divisions critical: No more oocytes made after
Primary oocytes remain in the first phase of meiosis until ovulation or cell death occurs
Primordial follicle
Oocyte surrounded by protective layers and cells
Surrounding cells condense around oocyte and differentiate into granulosa cells
Granulosa cells secrete basal lamina
Folliculogenesis
Growth and development of follicles from rest stages to ovulation
Oocyte secrete acellular layer-zona pellucida, stays attached after ovulation
Second layer of cells differentiate around basal layer to form theca cells
Follicle Growth
Driven mostly by FSH but early growth is independent of FSH
o Even with FSH suppression
• Rapid increase in Follicle diameter and increased Granulosa cell division lead to gaps to form between Granulosa layers
o Fluid-filled spaces forming an Antrum – Known as
Antral/Secondary Follicles
`Follicle Recruitment
Only follicles of sufficient size able to survive decrease in FSH (which occurs due to initial Negative Feedback from Oestrogen)
o Only one follicle from the pool will be selected for Ovulation and possible Fertilisation
Movement of sperm in female tract
Coagulation of seminal fluid to reduce sperm loss-liquefaction occurs later, sperm survive 24-48 hours in tract
Absence of progesterone means mucous is less viscous allowing sperm to pass
Movement through mucous leads to removal of seminal fluid and abnormal sperm
Sperm inhabit cervical crypts which act as a reservoir
Currents set up by uterine/tubal cilia, chemoattractant from oocyte cumulous complex
Sperm Capacitation
Biochemical arrangement of surface glycoproteins initiates whiplashing of sperm tail increasing progressive motility and preparing it for acrosomal reaction
Promoted through removal of sperm from seminal fluid, factors in uterine or tubal fluid
Fertilisation
Acrosomal membrane on the sperm head fuses when in close proximity to oocyte-release of enzymes which cut through outer layer of cumulus cells
Sperm head taken in by phagocytosis
Release of cortical granules of oocyte leading to hardening of oocyte to prevent polyspermy
Syngamy
Fusion of 2 gametes together
Entry of sperm causes oocyte intracellular Ca2+ influx
Oocyte completes meiosis 2 forming female pronucleus and expelling the second polar body
Break down of sperm nuclear membrane leading to decondensation of chromatin and separation of chromosomes forming male pronucleus and pronucleus membranes break down and first mitotic division occurs
Implantation
2 cell zygote, 4 cell, morula stage (8-16 cells, 3-4 days post), blastocyst stage
Zona hatching occurs in late blastocyst stage, loose apposition of blastyocyst with endometrial wall with direct contract with trophoblast and decidua leading to adhesion and invasion
Most common sites for ectopics: Tubal, cervical, ovarian or abdominal
Stats on Subfertility
1 in 6 couples seek specialist help
84% will achieve pregnancy in 1yr with regular UPSI, 92% within 2 years
Refer for specialist advice if at least 1 year of trying
Prompt investigations if known fertility issues, anovulatory cycles, severe endometriosis , previous PID, malignancy
Causes of subfertility
21% due to ovulation disorders 15-20% due to Tubal factors 6-8% Endometriosis 25% Male factors 28% Unexplained
Causes of Anovulation
Premature Ovarian Failure Turner's (Primary Amenorrhoea) Autoimmune Iatrogenic: Surgery/chemotherapy Secondary to PCOS Excessive weight loss or exercise Hypopituitarism Kallmann's Syndrome (Primary Hypogonadotropic Hypogonadism) Hyperprolactinaemia (Adenoma)
Assessment of Female Subfertility
Duration, menstrual cycle (regularity, LMP), pelvic pain (dysmenorrhoea, dyspareunia), cervical smear hx, previous pregnancies or ectopics, coital frequency
PMHx, PSHx, STIs, PID, DHx
Smoking, ETOH, Folic acid, rec drugs
Examine BMI, endocrine signs, pelvic exam, cervical smear and chlamydia screening
Investigations: Baseline (day 2-5) FSH, LH, TSH, Prolactin, Testosterone, Mid Luteal Progesterone
Assessment of Tubal Patency-Hysterosalpingography, Laparoscopy and Dye test or Hysterosalpingo contrast sonography
Lifestyle Modification for Female Subfertility
Healthy diet Stop smoking/drugs Reduce ETOH consumption Regular exercise Folic acid Avoid timed intercourse or ovulation induction kits
Antioestrogens
Clomifene on days 2-6
Increases endogenous FSH levels via negative feedback to pituitary
Increases rate of multiple pregnancies
SE: Hot flushes, mood lability
Limited to 12 cycles as ovarian cancer risk
GnRH
Used for low oestrogen, normal FSH or clomifene resistant PCOS
Multiple injections, expensive, requires US monitoring
Laparoscopic Ovarian Diathermy for PCOS
Part of ovarian tissue is destroyed
Decrease in level of androgens produced
Improve ovulation
Effects last 12-18 months if successful
Other Management of Female Subfertility
Surgical Management of Endometriosis (Laser, Diathermy, Excision) and Tubal (Microsurgery, Adhesiolysis); Preferably Laparoscopic to reduce risk of Adhesions
Male Subfertility
Normal male fertility is dependent on normal spermatogenesis, erectile function and ejaculation, normal semen analysis
Azoospermia
No sperm in ejaculate
Oligozoospermia
Reduced sperm in ejaculate
Investigating Male Subfertility
FSH: Raised in testicular failure
Karyotyping: Excluding Klinefelter’s
CF Screen: Exclude congenital absence of vas deferens
Review medications:
Stop Antispermatogenic: ETOH, Anabolic steroids, sulfasalazine
Antiandrogenic: Cimetidine, spironolactone
Drugs that contribute to erectile dysfunction:
Alpha or beta blockers, antidepressants, diuretics, metoclopramide
Causes of male subfertility:
Semen abnormalities
Idiopathic oligoasthenoteratozoospermia
Testicular cancer
Drugs
Varicoceles (Surgical treatment does not improve pregnancy rate)
Causes of subfertility:causes of Azoospermia
Anabolic steroids Hypogonadotropic hypogonadism Pituitary Adenoma Crypto-orchidism Orchiditis Chemoradiotherapy CBAVD Chalmydia Gonorrhoea
Causes of Subfertility: Immunological
Anti-sperm antibodies
Idiopathic
Causes of Subfertility:
Coital Dysfunction
Mechanical causes
Retrograde ejaculation
Failure to ejaculate
Indications for IVF
Used for in Tubal disease, male subfertility, endometriosis, anovulation, maternal age, unexplained infertility >2 years
Basal elevated FSH may indicate poor response to ovarian stimulation
Requires consent from HFEA and welfare of the child issues considered
How does IVF work
Luteal phase of previous cycle: Downregulation of ovaries using GnRH analogues
Ovarian stimulation: Recombinant FSH, monitored by TV USS
Follicular maturation by hCG when significant mature-sized follicles seen
Transvaginal oocyte retrieval by needle aspiration 36hours later
Sperm sample collected/thawed, prepared and cultured with oocytes
Fertilisation checks, embryo transfer through cervix on day2-3 or day 5
Maximum 2 embryos transferred in women <40 years
Surplus embryos may be cryopreserved for future cycles
Luteal support given in form of progestogens: Pregnancy test 2 weeks later
Intracytoplasmic Sperm Injection
For men with severely abnormal semen parameters; also for failed fertilisation in IVF cycles
o Sperm may be retrieved from Ejaculate, or Surgically from Epididymis
o Men with severe Oligozoospermia should have karyotype and CF screening prior
Preimplantation Genetic Diagnosis
Reduce Recurrence of Genetic Risk in couples with known Heritable conditions
• Allows for Embryo Biopsy, Single Cell Diagnosis, and Transfer of Unaffected Embryos into women; Biopsy usually done at Cleavage stage (Day 2-3)
o PCR or FISH used for genetic testing
Intrauterine Insemination
- Sperm is prepared and placed into Uterus to aid conception
- For mild Male Subfertility, Unexplained, Coital difficulties or Same-sex couples/Donor
- Optimal outcome happens within first 4 cycles; Unknown role of Ovarian Stimulation
Oocyte Donation
Strict criteria for gamete donation regulated by HFEA
Donor medical assessment, counselling, infectious screening, egg donors ideally under 35 yrs
For women with ovarian failure, older women >45 years or repeated IVF failure
Ovarian Hyperstimulation Syndrome
Complication of ovulation induction
Ovarian enlargement and shifting of fluid to extravascular space, accumulation in peritoneal and pleural spaces
Hypovolemia results in haemoconcentration and hypercoagulability
How to predict ovarian hyperstimulation syndrome
Prediction and active prevention
Lower dose GnRH, cycle cancellation, coasting during stimulation or elective embryo cryopreservation for use in further cycles, invitro maturation of follicles avoids OHSS
Management of Ovarian Hyperstimulation syndrome
Symptomatic relief Maintenance and assessment of hydration status, Chest and resp function Ascites and legs (Thrombotic risk) Fluid management Thromboprophylaxis Paracentesis +/- albumin replacement Analgesia Antiemetics
